Organic nitrates (nitric acid esters) have been proven useful in the therapy of cardiac diseases.
They act both by alleviating the before and after effects of a load on the heart, as well as through improvement of the oxygen supply to the heart by dilation of the coronary vessels.
In any case, it has been found in recent years that the organic nitrates which have been used so far in therapy, such as glycerol trinitrate (GTN), isosorbid-5-mononitrate or isosorbid dinitrate, because of nitrate tolerance, exhibit a clear drop in efficacy in a relatively short time when continuous high dosages are administered to the patient. Numerous experiments indicate that the presence of sulfhydryl (--SH) groups prevents the development of nitrate tolerance and that an existing tolerance can be reduced.
The development of tolerance is presently understood to be as follows:
According to the present state of knowledge, the pharmacological action of organic nitrate compounds depends on the presence of cysteine. The organic nitrate forms a common precursor with cysteine and, when it decomposes, --NO radicals among others, are liberated and activate soluble guanylate cyclase, the target enzyme, of the smooth muscle cells. Subsequent reactions triggered by the formation of cGMP lead to relaxation or dilation of the vessels.
The reactive and short-lived, and so far, only hypothetical intermediate product would have to be a thioester of nitric acid or a thionitrate. Through intramolecular rearrangement and other subsequent reactions which have not yet been established, the final formation of a nitroso thiol is postulated, from which nitrogen monoxide or nitrite ions are liberated. On the other hand, the enzyme-dependent degradation with the aid of GSH reductase would not be of significance for the pharmacological action, because it leads exclusively to the formation of nitrite ions. As already stated, the nonenzymatic degradation needs cysteine and can thus be exhausted in a dose-dependent manner (exhaustion of the SH group pool), so that over a long term sufficient NO, which is the actual activator of guanyl cyclase, can no longer be formed so that the clinical effectiveness will be reduced.